Agents of the reticulo-endothelial stimulant class have been widely used in order to augment the systemic host defenses against cancer. The most commonly used preparations have been live bacteria, such as Bacillus Calmette Guerin--BCG, dead bacteria such as Corynebacterium parvum or derivatives (Methanol extract residue--MER). These preparations have several undesirable properties. They are toxic, immunogenic; leading to potentially lethal allergic sequelae; and in the case of BCG, infective. As a result, a number of analogues, some of them synthetic, usually based on the active principle of an existing agent, for instance Muramyl dipeptide from BCG and glucan from yeasts, have been developed which are potentially of low toxicity and which are neither infective nor immunogenic.
The selection of compounds and preparations for clinical use cannot be made in the clinic and are based on the results of studies both on their toxicity and their anti-tumor effects. The conventional tests for anti-tumor effects are either prophylactic, that is the preparation is administered prior to challenge with a tumor, or therapeutic, in which the agent is administered after challenge with a tumor, using inbred strains of laboratory animals, typically mice.
The tumor may be injected locally, such as subcutaneously, or systemically, usually intravenously, in which case the tumor grows in organs such as the lungs or liver, which are known as the target organs. Occasionally, the effect on the metastatic spread to distant organs, from a local implant, is analyzed. The parameters which are measured by such conventional tests are: incidence of tumor, number of tumors, weights of tumors, and volumes of tumors.
The most biologically relevant method explores therapeutic effects on spontaneous metastases. The most sensitive method uses prophylaxis against an intravenous challenge with tumor cells. The former is a difficult model to handle. It is insensitive, seldom reproducible, and involves either counting of lung nodules, which is subjective, weighing of tumor, which is imprecise, or planimetric analysis of serial histological sections which is impractically time consuming and takes up to 60 days to complete. The latter is easier to reproduce and more sensitive, but uses the same inadequate methods of analysis and takes over 30 days to complete.
Both methods are further limited by the spread of data which, within an experimental group, is large. For example, the data spread typically produces ranges of high:low values of 10:1 or greater and this allows for very poor definition. As a practical result this means that such testing procedures require large numbers of animals within each group usually greater than 10. Consequently the number of experimental groups is limited, and the amount of useful information that can be obtained is likewise severely restricted.